The development of drug delivery routes remains an important element in the progress of the pharmaceutical sciences. Once an active compound has been identified, the design of delivery mechanisms must overcome challenges of transporting the medicament to the required site of action in the body whilst addressing issues including shelf life, bioavailability, toxicity, and patient compliance. All of these challenges must be overcome to achieve the desired therapeutic effect. Amongst the drug delivery options, oral administration is by far the most common route, with other options including injection, inhalation, topical or transmucosal administration.
The oral delivery route faces perhaps the most challenging route for a pharmaceutical to reach the final site of action: the composition is prone to loss from the mouth or stomach (e.g. by spitting or vomiting); the composition must survive the acidic and enzymatically-active environment of the stomach; if not absorbed in the stomach, the medicament must survive the action of bile salts and further intestinal and bacterial enzymatic action within the intestinal tract, be able to cross from the lumen of the gut to the intestinal wall for absorption, and then survive the degradation processes of the liver following transport by the hepatic portal system, often resulting in poor availability due to the first pass effect. In addition, some patients can't take (or don't like taking) tablets, a common form for oral dosing. Despite these challenges, the oral route of drug administration remains the most common.
Statins are HMG-CoA reductase inhibitors. HMG-CoA reductase is the rate-controlling enzyme in the biosynthesis of cholesterol in the liver. Thus statins can be used to lower cholesterol levels in an individual, especially those with hypercholesterolaemia. Increased cholesterol levels have been associated with cardiovascular disease and statins are therefore used in the prevention and management of such diseases. To date, statins have been administered exclusively orally, and a number of side-effect issues have arisen. Firstly, oral delivery provides quite variable levels of absorption for a particular statin dose, both intra-subject (possibly dependent on e.g. gastric content) and inter-subject. Secondly, a number of adverse effects have been reported, such as gastrointestinal adverse effects, raised liver enzymes and muscle problems—such as myalgias, myopathy and myositis. In the extreme, rhabdomyolysis with acute renal failure may occur.
It is among the objectives of the present invention to attempt a solution to these problems.